Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 35.455
Filtrar
1.
J Sci Food Agric ; 102(2): 575-583, 2022 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-34148247

RESUMO

BACKGROUND: Yeast hydrolysate (YH) has multiple salutary biological activities. Nevertheless, the application of YH in broiler production is limited. This study was conducted to evaluate the protective effects of YH derived from Saccharomyces cerevisiae by exploring growth performance, serum parameters, organs relative weight, carcass traits, meat quality and antioxidant status of broilers. RESULTS: Supplementing YH linearly and quadratically improved (P < 0.05) body weight gain and gain-to-feed ratio compared to that in the control group. Triglycerides, low-density lipoprotein cholesterol and total cholesterol in serum, the decline in pH and cooking loss of breast muscle, and malonaldehyde concentration in serum and liver were decreased linearly and/or quadratically by YH (P < 0.05), whereas high-density lipoprotein cholesterol in serum, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in serum, GSH-Px activity in liver, glutathione content in serum and liver, eviscerated yield rate and chest muscle yield, and the relative weight of spleen and liver were linearly and/or quadratically increased (P < 0.05). Moreover, YH enhanced the mRNA levels of nuclear factor erythroid 2-related factor 2, heme oxygennase-1 (HO-1), GSH-Px1 and SOD1 (linear and/or quadratic, P < 0.05). CONCLUSION: Dietary YH beneficially affected growth performance, serum parameters, organ relative weight, carcass traits, meat quality and antioxidant status in broilers, indicating its potential application as a promising feed additive in broiler production. © 2021 Society of Chemical Industry.


Assuntos
Antioxidantes/metabolismo , Galinhas/crescimento & desenvolvimento , Suplementos Nutricionais/análise , Carne/análise , Hidrolisados de Proteína/análise , Saccharomyces cerevisiae/química , Ração Animal/análise , Animais , Peso Corporal , Galinhas/sangue , Galinhas/metabolismo , Colesterol/sangue , Glutationa/metabolismo , Malondialdeído/metabolismo , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Hidrolisados de Proteína/metabolismo , Superóxido Dismutase/metabolismo , Triglicerídeos/sangue
2.
J Colloid Interface Sci ; 606(Pt 2): 1586-1596, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34500160

RESUMO

Hyaluronic acid (HA), a natural polymer, has gained much attention recently because of its good biocompatibility and extensive availability. Herein, a novel drug delivery system based on hyaluronic acid-tetraphenyl ethylene conjugate (HA-SS-TPE) with glutathione (GSH)-responsiveness for targeted drug delivery is designed. During the self-assembly of HA-SS-TPE, doxorubicin (DOX) is loaded to form DOX-loaded polymeric micelles. These as-prepared DOX-loaded polymeric micelles not only exhibit fluorescent emission, but also fast glutathione-triggered dissociation to unload DOX by responding to tumor microenvironments. In-vitro investigations showed that the DOX-loaded polymeric micelles presented a higher intracellular release ratio in CD44-positive cells (ES2 and Hela) than in CD44-negative cells (MCF-7 and L929). Notably, in vivo investigations showed that DOX@HA-SS-TPE significantly suppressed tumor growth. As a result, such a GSH-responsive drug delivery system with fluorescent feature provides a potential treatment for CD44-overexpressing cancers.


Assuntos
Antineoplásicos , Sistemas de Liberação de Medicamentos , Ácido Hialurônico , Micelas , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Glutationa/metabolismo , Células HeLa , Humanos , Concentração de Íons de Hidrogênio
3.
Biol Trace Elem Res ; 200(1): 147-155, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33689144

RESUMO

Hypercapnia can increase the production of reactive oxygen species (ROS) by inducing oxidative stress in cells. Transient receptor potential melastatin 2 (TRPM2) channel activation that is realized by ROS plays a critical role in the cellular mechanism. It was shown that antioxidants such as zinc (Zn), selenium (Se), and glutathione (GSH) can partake in the structures of enzymes and create a protective effect against oxidative stress. This study revealed the relationship between TRPM2 channel and hypercapnia, and the interaction of zinc, selenium, and glutathione. In our study, normoxia, hypercapnia, hypercapnia + Zn, hypercapnia + Se, and hypercapnia + GSH were created, in transfected HEK293 cells. The cells were exposed to normoxia or hypercapnia gasses in two different times (30 min and 60 min), while Zn, Se, and GSH were applied to the cells in the other groups before being exposed to the gas mixtures. The statistical evaluation showed a significant increase in lipid peroxidation (LPO) level and lactate dehydrogenase (LDH)% in the hypercapnia 30 min and 60 min groups, compared to the normoxia 30 min and 60 min groups, and an increase in LPO level and LDH% in the hypercapnia groups that Zn, Se, and GSH were applied. It was determined that in comparison with the normoxia 30 min and 60 min groups, the amount of inward Ca+2 current across TRPM2 channels and mean current density increased in the groups that were exposed to hypercapnia for 30 min and 60 min, while the same values significantly decreased in the hypercapnia groups that Zn, Se, and GSH were applied. Also, it was shown that oxidative stress rose as the duration of hypercapnia exposure increased. It was concluded that hypercapnia increased oxidative stress and caused cellular membrane damage, while the addition of Zn, Se, and GSH could protect the cell membrane from these damaging effects.


Assuntos
Acidose , Selênio , Canais de Cátion TRPM , Glutationa/metabolismo , Células HEK293 , Humanos , Zinco
4.
Methods Mol Biol ; 2363: 199-213, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34545495

RESUMO

Mitochondria actively participate in oxygenic metabolism and are one of the major sources of reactive oxygen species (ROS) production in plant cells. However, instead of measuring ROS concentrations in organelles it is more worthwhile to observe active ROS generation or downstream oxidation products, because the steady state level of ROS is easily buffered. Here, we describe how to measure the in vitro production of superoxide anion radicals (O2·-) by mitochondria and the release of O2·- into the cytosol. A method to determine glutathione, which is the most abundant mitochondrial low-mass antioxidant, is presented since changes in the redox state of glutathione can be indicative of the oxidative action of ROS. The identification of oxidative damage to mitochondrial components is the ultimate symptom that ROS homeostasis is not under control. We present how to determine the extent of oxidation of membrane lipids and the carbonylation of mitochondrial proteins. In summary, oxidative stress symptoms have to be analyzed at different levels, including ROS production, scavenging capacity, and signs of destruction, which only together can be considered markers of mitochondrial ROS status.


Assuntos
Mitocôndrias , Estresse Oxidativo , Glutationa/metabolismo , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
5.
Sci Total Environ ; 806(Pt 2): 150703, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34600989

RESUMO

1,4-Dioxane (DX) is a synthetic chemical used as a stabilizer for industrial solvents. Recent occurrence data show widespread and significant contamination of drinking water with DX in the US. DX is classified by the International Agency for Research on Cancer as a group 2B carcinogen with the primary target organ being the liver in animal studies. Despite the exposure and cancer risk, US EPA has not established a drinking water Maximum Contaminant Level (MCL) for DX and a wide range of drinking water targets have been established across the US and by Health Canada. The DX carcinogenic mechanism remains unknown; this information gap contributes to the varied approaches to its regulation. Our recent mice study indicated alterations in oxidative stress response accompanying DNA damage as an early change by high dose DX (5000 ppm) in drinking water. Herein, we report a follow-up study, in which we used glutathione (GSH)-deficient glutamate-cysteine ligase modifier subunit (Gclm)-null mice to investigate the role of redox homeostasis in DX-induced liver cytotoxicity and genotoxicity. Gclm-null and wild-type mice were exposed to DX for one week (1000 mg/kg/day by oral gavage) or three months (5000 ppm in drinking water). Subchronic exposure of high dose DX caused mild liver cytotoxicity. DX induced assorted molecular changes in the liver including: (i) a compensatory nuclear factor erythroid 2-related factor 2 (NRF2) anti-oxidative response at the early stage (one week), (ii) progressive CYP2E1 induction, (iii) development of oxidative stress, as evidenced by persistent NRF2 induction, oxidation of GSH pool, and accumulation of the lipid peroxidation by-product 4-hydroxynonenal, and (iv) elevations in oxidative DNA damage and DNA repair response. These DX-elicited changes were exaggerated in GSH-deficient mice. Collectively, the current study provides additional evidence linking redox dysregulation to DX liver genotoxicity, implying oxidative stress as a candidate mechanism of DX liver carcinogenicity.


Assuntos
Dano ao DNA , Estresse Oxidativo , Animais , Dioxanos , Seguimentos , Glutationa/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Knockout
6.
Endocrinology ; 163(1)2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34647995

RESUMO

Seminal plasma contains a high concentration of extracellular vesicles (EVs). The heterogeneity of small EVs or the presence of nonvesicular extracellular matter (NV) pose major obstacles in understanding the composition and function of seminal EVs. In this study, we employed high-resolution density gradient fractionation to accurately characterize the composition and function of seminal EVs and NV. We found that the seminal EVs could be divided into 3 different subtypes-namely, high-density EV (EV-H), medium-density EV (EV-M), and low-density EV (EV-L)-after purification using iodixanol, while NV was successfully isolated. EVs and NV display different features in size, shape, and expression of some classic exosome markers. Both EV-H and NV could markedly promote sperm motility and capacitation compared with EV-M and EV-L, whereas only the NV fraction induced sperm acrosome reaction. Proteomic analysis results showed that EV-H, EV-M, EV-L, and NV had different protein components and were involved in different physiological functions. Further study showed that EV-M might reduce the production of sperm intrinsic reactive oxygen species through glutathione S-transferase mu 2. This study provides novel insights into important aspects of seminal EVs constituents and sounder footing to explore their functional properties in male fertility.


Assuntos
Vesículas Extracelulares/metabolismo , Proteômica/métodos , Sêmen/metabolismo , Motilidade Espermática , Reação Acrossômica , Biomarcadores/metabolismo , Biotinilação , Biologia Computacional , Exossomos/metabolismo , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Humanos , Masculino , Fosforilação , Proteínas Tirosina Fosfatases/química , Proteoma , Espécies Reativas de Oxigênio , Espermatozoides/metabolismo , Espermatozoides/fisiologia , Ácidos Tri-Iodobenzoicos/farmacologia
7.
J Cell Biol ; 221(2)2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-34817556

RESUMO

Ferroptosis is an oxidative and iron-dependent form of regulated cell death (RCD) recently described in eukaryotic organisms like animals, plants, and parasites. Here, we report that a similar process takes place in the photosynthetic prokaryote Synechocystis sp. PCC 6803 in response to heat stress. After a heat shock, Synechocystis sp. PCC 6803 cells undergo a cell death pathway that can be suppressed by the canonical ferroptosis inhibitors, CPX, vitamin E, Fer-1, liproxstatin-1, glutathione (GSH), or ascorbic acid (AsA). Moreover, as described for eukaryotic ferroptosis, this pathway is characterized by an early depletion of the antioxidants GSH and AsA, and by lipid peroxidation. These results indicate that all of the hallmarks described for eukaryotic ferroptosis are conserved in photosynthetic prokaryotes and suggest that ferroptosis might be an ancient cell death program.


Assuntos
Cianobactérias/citologia , Cianobactérias/metabolismo , Ferroptose , Ferro/metabolismo , Antioxidantes/metabolismo , Ácido Ascórbico/metabolismo , Cálcio/metabolismo , Caspase 3/metabolismo , Caspase 7/metabolismo , Citosol/metabolismo , Glutationa/metabolismo , Resposta ao Choque Térmico , Lipidômica , Lipídeos/química , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Synechocystis/metabolismo , Tilacoides/metabolismo
8.
J Hazard Mater ; 424(Pt A): 127310, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-34879548

RESUMO

The current study was designed to assess nanomaterial sulfonated graphene oxide (SGO) potential in improving tolerance of wheat chloroplasts against nitrate (NS) and ammonium (AS) toxicity. Triticum aestivum cv. Ekiz was grown under SGOs (50-250-500 mg L-1) with/without 140 mM NS and 5 mM AS stress. SGOs were eliminated the adverse effects produced by stress on chlorophyll fluorescence, potential photochemical efficiency and physiological state of the photosynthetic apparatus. SGO reversed the negative effects on these parameters. Upon SGOs exposure, the induced expression levels of photosystems-related reaction center proteins were observed. SGOs reverted radical accumulation triggered by NS by enabling the increased superoxide dismutase (SOD) activity and ascorbate (AsA) regeneration. Under AS, the turnover of both AsA and glutathione (GSH) was maintained by 50-250 mg L-1 SGO by increasing the enzymes and non-enzymes related to AsA-GSH cycle. 500 mg L-1 SGO prevented the radical over-accumulation produced by AS via the regeneration of AsA and peroxidase (POX) activity rather than GSH regeneration. 50-250 mg L-1 SGO protected from the NS+AS-induced disruptions through the defense pathways connected with AsA-GSH cycle represented the high rates of AsA/DHA and, GSH/GSSG and GSH redox state. Our findings specified that SGO to NS and AS-stressed wheat provides a new potential tool to advance the tolerance mechanism.


Assuntos
Compostos de Amônio , Nanoestruturas , Compostos de Amônio/metabolismo , Antioxidantes/metabolismo , Ácido Ascórbico/metabolismo , Cloroplastos/metabolismo , Glutationa/metabolismo , Grafite , Nitratos/metabolismo , Oxirredução , Triticum/metabolismo
9.
Ecotoxicol Environ Saf ; 229: 113111, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34952378

RESUMO

Acrolein (ACR) is a metabolic byproduct in vivo and a ubiquitous environmental toxicant. It is implicated in the initiation and development of many diseases through multiple mechanisms, including the induction of oxidative stress. Currently, our understanding of the body defense mechanism against ACR toxicity is still limited. Given that hydrogen sulfide (H2S) has strong antioxidative actions and it shares several properties of ACR scavenger glutathione (GSH), we, therefore, tested whether H2S could be involved in ACR detoxification. Taking advantage of two cell lines that produced different levels of endogenous H2S, we found that the severity of ACR toxicity was reversely correlated with H2S-producing ability. In further support of the role of H2S, supplementing cells with exogenous H2S increased cell resistance to ACR, whereas inhibition of endogenous H2S sensitized cells to ACR. In vivo experiments showed that inhibition of endogenous H2S with CSE inhibitor markedly increased mouse susceptibility to the toxicity of cyclophosphamide and ACR, as evidenced by the increased mortality and worsened organ injury. Further analysis revealed that H2S directly reacted with ACR. It promoted ACR clearance and prevented ACR-initiated protein carbonylation. Collectively, this study characterized H2S as a presently unrecognized endogenous scavenger of ACR and suggested that H2S can be exploited to prevent and treat ACR-associated diseases.


Assuntos
Sulfeto de Hidrogênio , Acroleína/toxicidade , Animais , Antioxidantes , Glutationa/metabolismo , Sulfeto de Hidrogênio/toxicidade , Camundongos , Estresse Oxidativo
10.
BMC Plant Biol ; 21(1): 593, 2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34906076

RESUMO

BACKGROUND: Light quality severely affects biosynthesis and metabolism-associated process of glutathione. However, the role of specific light is still unclear on the glutathione metabolism. In this article, comparatively transcriptome and metabolome methods are used to fully understand the blue and red-light conditions working on the glutathione metabolism in maize seedling leaf. RESULTS: There are 20 differently expressed genes and 4 differently expressed metabolites in KEGG pathway of glutathione metabolism. Among them, 12 genes belong to the glutathione S-transferase family, 3 genes belong to the ascorbate peroxidase gene family and 2 genes belong to the ribonucleoside-diphosphate reductase gene family. Three genes, G6PD, SPDS1, and GPX1 belong to the gene family of glucose 6-phosphate dehydrogenase, spermidine synthase, and glutathione peroxidase, respectively. Four differently expressed metabolites are identified. Three of them, Glutathione disulfide, Glutathione, and l-γ-Glutamyl-L-amino acid are decreased while L-Glutamate is increased. In addition, Through PPI analysis, two annotated genes gst16 and DAAT, and 3 unidentified genes 100381533, pco105094 and umc2770, identified as RPP13-like3, BCAT-like1and GMPS, were obtained. By the analysis of protein sequence and PPI network, we predict that pco105094 and umc2770 were involved in the GSSG-GSH and AsA-GSH cycle in the network of glutathione metabolism. CONCLUSIONS: Compared to red light, blue light remarkably changed the transcription signal transduction and metabolism of glutathione metabolism. Differently expressed genes and metabolic mapped to the glutathione metabolism signaling pathways. In total, we obtained three unidentified genes, and two of them were predicted in current glutathione metabolism network. This result will contribute to the research of glutathione metabolism of maize.


Assuntos
Glutationa/metabolismo , Redes e Vias Metabólicas/genética , Zea mays/metabolismo , Zea mays/efeitos da radiação , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Luz , Metaboloma , Folhas de Planta/enzimologia , Folhas de Planta/metabolismo , Folhas de Planta/efeitos da radiação , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Conformação Proteica , Plântula/metabolismo , Plântula/efeitos da radiação , Transcriptoma , Zea mays/enzimologia , Zea mays/genética
11.
Acta Cir Bras ; 36(11): e361108, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34932672

RESUMO

PURPOSE: To evaluate the oxidative stress in swine neonates submitted to hypoxia. METHODS: Ten large white piglets, healthy newborns, of both sexes, were divided into two groups and submitted to an experimental hypoxia protocol with reduced inspired oxygen fraction. The hypoxia group, composed of six animals, was submitted to oxygen reduction for 180 min. The animals in the control group, n = 4, were handled and evaluated simultaneously, but without oxygen reduction. RESULTS: 180 min after the start of the hypoxic insult, a significant difference was observed in the oximetry, and heart rate of the hypoxia group was compared to the control group (p<0.05). There was no significant difference in the oxidative stress analyses. Reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), lipid peroxidation (TBARS), protein carbonyl (PC), and myeloperoxidase (MPO) in the piglets' brain tissue were analyzed. CONCLUSIONS: Hypoxia causes adverse effects in swine neonates, although there is a natural physiological resistance of swine neonates to respond to this insult. Analyses of GSH, SOD, CAT, TBARS, MPO, and PC were tabulated and are presented as parameters for further studies to be carried out on an animal model of swine hypoxia.


Assuntos
Estresse Oxidativo , Superóxido Dismutase , Animais , Catalase/metabolismo , Modelos Animais de Doenças , Feminino , Glutationa/metabolismo , Hipóxia , Peroxidação de Lipídeos , Masculino , Superóxido Dismutase/metabolismo , Suínos , Substâncias Reativas com Ácido Tiobarbitúrico
12.
Cells ; 10(12)2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34943896

RESUMO

Cardiovascular diseases (CVD) are a leading cause of mortality worldwide, and dietary habits represent a major risk factor for dyslipidemia; a hallmark of CVD. Saturated fatty acids contribute to CVD by aggravating dyslipidemia, and, in particular, lauric acid (LA) raises circulating cholesterol levels. The role of red blood cells (RBCs) in CVD is increasingly being appreciated, and eryptosis has recently been identified as a novel mechanism in CVD. However, the effect of LA on RBC physiology has not been thoroughly investigated. RBCs were isolated from heparin-anticoagulated whole blood (WB) and exposed to 50-250 µM of LA for 24 h at 37 °C. Hemoglobin was photometrically examined as an indicator of hemolysis, whereas eryptosis was assessed by Annexin V-FITC for phosphatidylserine (PS) exposure, Fluo4/AM for Ca2+, light scatter for cellular morphology, H2DCFDA for oxidative stress, and BODIPY 581/591 C11 for lipid peroxidation. WB was also examined for RBC, leukocyte, and platelet viability and indices. LA caused dose-responsive hemolysis, and Ca2+-dependent PS exposure, elevated erythrocyte sedimentation rate (ESR), cytosolic Ca2+ overload, cell shrinkage and granularity, oxidative stress, accumulation of lipid peroxides, and stimulation of casein kinase 1α (CK1α). In WB, LA disrupted leukocyte distribution with elevated neutrophil-lymphocyte ratio (NLR) due to selective toxicity to lymphocytes. In conclusion, this report provides the first evidence of the pro-eryptotic potential of LA and associated mechanisms, which informs dietary interventions aimed at CVD prevention and management.


Assuntos
Cálcio/metabolismo , Gorduras na Dieta/farmacologia , Eriptose/efeitos dos fármacos , Ácidos Graxos/farmacologia , Ácidos Láuricos/farmacologia , Benzamidas/farmacologia , Espaço Extracelular/química , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Hemólise/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Humanos , Imidazóis/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilserinas/metabolismo , Carbonilação Proteica/efeitos dos fármacos
13.
PLoS One ; 16(12): e0260130, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34965258

RESUMO

The objective of the current study is to investigate the effect of rice bran oil (RBO) on hepatic fibrosis as a characteristic response to persistent liver injuries. Rats were randomly allocated into five groups: the negative control group, thioacetamide (TAA) group (thioacetamide 100 mg/kg thrice weekly for two successive weeks, ip), RBO 0.2 and 0.4 groups (RBO 0.2mL and 0.4 mL/rat/day, po) and standard group (silymarin 100 mg/kg/day, po) for two weeks after TAA injection. Blood and liver tissue samples were collected for biochemical, molecular, and histological analyses. Liver functions, oxidative stress, inflammation, liver fibrosis markers were assessed. The obtained results showed that RBO reduced TAA-induced liver fibrosis and suppressed the extracellular matrix formation. Compared to the positive control group, RBO dramatically reduced total bilirubin, AST, and ALT blood levels. Furthermore, RBO reduced MDA and increased GSH contents in the liver. Simultaneously RBO downregulated the NF-κß signaling pathway, which in turn inhibited the expression of some inflammatory mediators, including Cox-2, IL-1ß, and TNF-α. RBO attenuated liver fibrosis by suppressing the biological effects of TGF-ß1, α-SMA, collagen I, hydroxyproline, CTGF, and focal adhesion kinase (FAK). RBO reduced liver fibrosis by inhibiting hepatic stellate cell activation and modulating the interplay among the TGF-ß1 and FAK signal transduction. The greater dosage of 0.4 mL/kg has a more substantial impact. Hence, this investigation presents RBO as a promising antifibrotic agent in the TAA model through inhibition of TGF-ß1 /FAK/α-SMA.


Assuntos
Actinas/metabolismo , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Óleo de Farelo de Arroz/uso terapêutico , Fator de Crescimento Transformador beta1/metabolismo , Albuminas/metabolismo , Animais , Becaplermina/metabolismo , Biomarcadores/metabolismo , Colágeno Tipo I/metabolismo , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Cromatografia Gasosa-Espectrometria de Massas , Globulinas/metabolismo , Glutationa/metabolismo , Hidroxiprolina/metabolismo , Mediadores da Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/induzido quimicamente , Masculino , Malondialdeído/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Óleo de Farelo de Arroz/farmacologia , Transdução de Sinais/efeitos dos fármacos , Tioacetamida , Transaminases/sangue , Transaminases/metabolismo
14.
Int J Mol Sci ; 22(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34639126

RESUMO

Liver-specific deficiency of B-cell receptor-associated protein 31 knockout mice (BAP31-LKO) and the littermates were injected with acetaminophen (APAP), markers of liver injury, and the potential molecular mechanisms were determined. In response to APAP overdose, serum aspartate aminotransferase and alanine aminotransferase levels were increased in BAP31-LKO mice than in wild-type controls, accompanied by enhanced liver necrosis. APAP-induced apoptosis and mortality were increased. Hepatic glutathione was decreased (1.60 ± 0.31 µmol/g tissue in WT mice vs. 0.85 ± 0.14 µmol/g tissue in BAP31-LKO mice at 6 h, p < 0.05), along with reduced glutathione reductase activity and superoxide dismutase; while malondialdehyde was significantly induced (0.41 ± 0.03 nmol/mg tissue in WT mice vs. 0.50 ± 0.05 nmol/mg tissue in BAP31-LKO mice for 6 h, p < 0.05). JNK signaling activation and APAP-induced hepatic inflammation were increased in BAP31-LKO mice. The mechanism research revealed that BAP31-deficiency decreased Nrf2 mRNA stability (half-life of Nrf2 mRNA decreased from ~1.3 h to ~40 min) and miR-223 expression, led to reduced nuclear factor erythroid 2-related factor 2 (Nrf2) signaling activation and antioxidant genes induction. BAP31-deficiency decreased mitochondrial membrane potentials, reduced mitochondria-related genes expression, and resulted in mitochondrial dysfunction in the liver. Conclusions: BAP31-deficiency reduced the antioxidant response and Nrf2 signaling activation via reducing Nrf2 mRNA stabilization, enhanced JNK signaling activation, hepatic inflammation, and apoptosis, amplified APAP-induced hepatotoxicity in mice.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/patologia , Proteínas de Membrana/fisiologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Animais , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Glutationa/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
15.
Biochem J ; 478(20): 3741-3756, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34605540

RESUMO

The cystic fibrosis transmembrane conductance regulator (CFTR) gene lies within a topologically associated domain (TAD) in which multiple cis-regulatory elements (CREs) and transcription factors (TFs) regulate its cell-specific expression. The CREs are recruited to the gene promoter by a looping mechanism that depends upon both architectural proteins and specific TFs. An siRNA screen to identify TFs coordinating CFTR expression in airway epithelial cells suggested an activating role for BTB domain and CNC homolog 1 (BACH1). BACH1 is a ubiquitous master regulator of the cellular response to oxidative stress. Here, we show that BACH1 may have a dual effect on CFTR expression by direct occupancy of CREs at physiological oxygen (∼8%), while indirectly modulating expression under conditions of oxidative stress. Hence BACH1, can activate or repress the same gene, to fine tune expression in response to environmental cues such as cell stress. Furthermore, our 4C-seq data suggest that BACH1 can also directly regulate CFTR gene expression by modulating locus architecture through occupancy at known enhancers and structural elements, and depletion of BACH1 alters the higher order chromatin structure.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Estresse Oxidativo/genética , Fatores de Transcrição de Zíper de Leucina Básica/antagonistas & inibidores , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Perfilação da Expressão Gênica , Glutamato-Cisteína Ligase/genética , Glutamato-Cisteína Ligase/metabolismo , Glutationa/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Oxigênio/metabolismo , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
16.
Redox Biol ; 47: 102160, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34624602

RESUMO

BACKGROUND: Interleukin-1-dependent increases in glycolysis promote allergic airways disease in mice and disruption of pyruvate kinase M2 (PKM2) activity is critical herein. Glutathione-S-transferase P (GSTP) has been implicated in asthma pathogenesis and regulates the oxidation state of proteins via S-glutathionylation. We addressed whether GSTP-dependent S-glutathionylation promotes allergic airways disease by promoting glycolytic reprogramming and whether it involves the disruption of PKM2. METHODS: We used house dust mite (HDM) or interleukin-1ß in C57BL6/NJ WT or mice that lack GSTP. Airway basal cells were stimulated with interleukin-1ß and the selective GSTP inhibitor, TLK199. GSTP and PKM2 were evaluated in sputum samples of asthmatics and healthy controls and incorporated analysis of the U-BIOPRED severe asthma cohort database. RESULTS: Ablation of Gstp decreased total S-glutathionylation and attenuated HDM-induced allergic airways disease and interleukin-1ß-mediated inflammation. Gstp deletion or inhibition by TLK199 decreased the interleukin-1ß-stimulated secretion of pro-inflammatory mediators and lactate by epithelial cells. 13C-glucose metabolomics showed decreased glycolysis flux at the pyruvate kinase step in response to TLK199. GSTP and PKM2 levels were increased in BAL of HDM-exposed mice as well as in sputum of asthmatics compared to controls. Sputum proteomics and transcriptomics revealed strong correlations between GSTP, PKM2, and the glycolysis pathway in asthma. CONCLUSIONS: GSTP contributes to the pathogenesis of allergic airways disease in association with enhanced glycolysis and oxidative disruption of PKM2. Our findings also suggest a PKM2-GSTP-glycolysis signature in asthma that is associated with severe disease.


Assuntos
Asma , Piruvato Quinase , Animais , Glutationa/metabolismo , Glutationa Transferase , Glicólise , Pulmão/metabolismo , Camundongos , Piruvato Quinase/genética , Piruvato Quinase/metabolismo
17.
FASEB J ; 35(11): e21854, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34597422

RESUMO

Ammonia is one of the major metabolites produced by intestinal microorganisms; however, its role in intestinal homeostasis is poorly understood. The present study investigated the regulation of intestinal tight junction (TJ) proteins by ammonia and the underlying mechanisms in human intestinal Caco-2 cells. Ammonia (15, 30, and 60 mM) increased the permeability of the cells in a dose-dependent manner, as indicated by reduced transepithelial electrical resistance and increased dextran flux. Immunoblot and immunofluorescence analyses revealed that the ammonia-induced increase in TJ permeability reduced the membrane localization of TJ proteins such as zonula occludens (ZO)1, ZO2, occludin, claudin-1, and claudin-3. DNA microarray analysis identified a biological pathway "response to reactive oxygen species" enriched by ammonia treatment, indicating the induction of oxidative stress in the cells. Ammonia treatment also increased the malondialdehyde content and decreased the ratio of reduced to oxidized glutathione. Meanwhile, ammonia treatment-induced mitochondrial dysfunction, as indicated by the downregulation of genes associated with the electron transport chain, reduction of the cellular ATP, NADH, and tricarboxylic acid cycle intermediate content, and suppression of the mitochondrial membrane potential. In contrast, N-acetyl cysteine reversed the ammonia-induced impairment of TJ permeability and structure without affecting the mitochondrial parameters. Collectively, ammonia impaired the TJ barrier by increasing oxidative stress in Caco-2 cells. A mitochondrial dysfunction is possibly an event preceding ammonia-induced oxidative stress. The findings of this study could potentially improve our understanding of the interplay between intestinal microorganisms and their hosts.


Assuntos
Amônia/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/metabolismo , Trifosfato de Adenosina/metabolismo , Células CACO-2 , Glutationa/metabolismo , Humanos , Interleucina-8/biossíntese , Mucosa Intestinal/metabolismo , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , NADP/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Insuficiência Renal Crônica/metabolismo
18.
Life Sci ; 285: 120003, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34599936

RESUMO

AIMS: Indole-3-propionic acid (IPA) is a natural product from human microbiota, exhibiting diverse biological activities. The study focused on investigating the antibacterial mode of action(s) triggered by IPA in Escherichia coli. Separate influence of nitric oxide (NO) and each reactive oxygen species, including superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxyl radical (OH-), was specifically analyzed throughout the process. MAIN METHODS: The generation of respective reactive oxygen species (ROS), NO, and ONOO- was conducted using flow cytometer using different dyes. Further analysis of separate influences was held based on usage of each scavenger: sodium pyruvate, thiourea, tiron, and L-NAME. Oxidative cell damage was observed through the detection of glutathione depletion and lipid peroxidation. DNA fragmentation and membrane depolarization were observed by TUNEL and DiBAC4(3) staining agent. Finally, Annexin V/PI and FITC-VAD-FMK were applied to detect apoptosis-like death. KEY FINDINGS: IPA exhibited antibacterial activity in E. coli through the accumulation of ROS, NO, ONOO-, and DNA damage, eventually leading to apoptosis-like death. NO and O2- exerted the most potent influence on oxidative damage of E. coli, whereas H2O2 accounts for the least impact. Moreover, the results reveal the major contribution of ONOO- in IPA-induced apoptosis-like death in E. coli. SIGNIFICANCE: This is the first study that introduces the antibacterial activity and apoptosis-like death induced by IPA and suggests the possibility of being an alternative for current antibiotics. Furthermore, the distinct influence of each ROS and NO was analyzed to investigate their contribution to oxidative damage leading to bacterial apoptosis-like death.


Assuntos
Antibiose , Apoptose , Escherichia coli/fisiologia , Indóis/metabolismo , Microbiota/fisiologia , Óxido Nítrico/fisiologia , Propionatos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fragmentação do DNA , Escherichia coli/efeitos dos fármacos , Glutationa/metabolismo , Indóis/farmacologia , Peroxidação de Lipídeos , Microbiota/efeitos dos fármacos , Propionatos/farmacologia
19.
Elife ; 102021 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-34632981

RESUMO

Gut enzymes can metabolize plant defense compounds and thereby affect the growth and fitness of insect herbivores. Whether these enzymes also influence feeding preference is largely unknown. We studied the metabolization of taraxinic acid ß-D-glucopyranosyl ester (TA-G), a sesquiterpene lactone of the common dandelion (Taraxacum officinale) that deters its major root herbivore, the common cockchafer larva (Melolontha melolontha). We have demonstrated that TA-G is rapidly deglucosylated and conjugated to glutathione in the insect gut. A broad-spectrum M. melolontha ß-glucosidase, Mm_bGlc17, is sufficient and necessary for TA-G deglucosylation. Using cross-species RNA interference, we have shown that Mm_bGlc17 reduces TA-G toxicity. Furthermore, Mm_bGlc17 is required for the preference of M. melolontha larvae for TA-G-deficient plants. Thus, herbivore metabolism modulates both the toxicity and deterrence of a plant defense compound. Our work illustrates the multifaceted roles of insect digestive enzymes as mediators of plant-herbivore interactions.


Assuntos
Besouros/enzimologia , Glucosídeos/metabolismo , Herbivoria , Proteínas de Insetos/metabolismo , Lactonas/metabolismo , Sesquiterpenos/metabolismo , Taraxacum/metabolismo , beta-Galactosidase/metabolismo , Animais , Besouros/embriologia , Besouros/genética , Digestão , Glucosídeos/toxicidade , Glutationa/metabolismo , Hidrólise , Inativação Metabólica , Proteínas de Insetos/genética , Lactonas/toxicidade , Larva/enzimologia , Larva/genética , Metabolismo Secundário , Sesquiterpenos/toxicidade , Taraxacum/toxicidade , beta-Galactosidase/genética
20.
Chem Biol Interact ; 350: 109701, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34656557

RESUMO

Acrylamide (AA) is classified as a probable human carcinogen and is ubiquitous in foods processed at high temperatures. The carcinogenicity of AA has been attributed to its active metabolite, glycidamide (GA). Both AA and GA can spontaneously or enzymatically conjugate with glutathione (GSH) to form their corresponding GSH conjugates. Profiling AA-glutathione conjugate (AA-GSH) and GA-glutathione conjugates (2 isomers: GA2-GSH and GA3-GSH) in serum would better illustrate AA detoxification compared with urinary metabolite analysis. However, the lack of AA-, GA2, and GA3-GSH study remains a critical data gap. Our study aimed to investigate the toxicokinetics of AA-, GA2-and GA3-GSH in Sprague Dawley rats treated with 0.1 mg/kg, 1.0 mg/kg, or 5.0 mg/kg AA. Blood samples were collected for LC-MS/MS analysis of the GSH conjugate products. Within 24 h of treatment, we observed rapid formation, elimination, and linear kinetics of AA-, GA2-and GA3-GSH. The ∑GA-GSH AUC/AA-GSH AUC ratios were 0.14-0.29, similar to ∑GA/AA AUC in serum but different from ∑GA/AA-derived urinary mercapturic acids in rodents. Our analysis of AA- and GA-GSHs values represents direct detoxification of AA and GA in vivo. This study advances our understanding of sex and inter-species differences in AA detoxification and may refine the existing kinetic models for a more relevant risk extrapolation.


Assuntos
Acrilamida/toxicidade , Glutationa/análogos & derivados , Acrilamida/química , Acrilamida/metabolismo , Animais , Carcinógenos/química , Carcinógenos/metabolismo , Carcinógenos/toxicidade , Compostos de Epóxi/química , Compostos de Epóxi/metabolismo , Compostos de Epóxi/toxicidade , Feminino , Glutationa/metabolismo , Glutationa/toxicidade , Humanos , Masculino , Redes e Vias Metabólicas , Modelos Biológicos , Ratos , Ratos Sprague-Dawley , Toxicocinética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA